Organometallic compounds containing 1, 3, 5-triazine rings



Patented Nov. 11, 1947 UNITED STATES PATENT OFFICE ORGAN OMETALLIC COMPOUNDS CONTAIN ING 1,3,5-TRIAZINE RINGS- Ernst A. H. Friedheim, New York, N. Y.

No Drawing. Application May 19, 1944, Serial No. 536,425

Claims. (01. 260-242;)

The compounds according to the present invention correspond to the general formula I 0 l c s nix N l Sb=D said formula representing new compounds consisting of a 1,3,5-triazine ring, at least one carbon atom of which is linked by a NH group to a phenyl-radical carrying a, trivalent antimonyradical or to a substituted phenyl-radical carrying a trivalent antimony radical. D represents a divalent radical selected from the group consisting of O, S, dihalides, radicals of the formula and sulfur-containing groups of the type=(fSR)z, wherein SR is the residue of a sulfhydril com.- pound of the type HS R, and R is selected from the group consisting of aliphatic and, cyclic radicals. Such sulfur-containing, compounds are, for example, thioglycoli'c acid, cysteine, gluthatione, thiophenoL thioacetic acid, thiobenzoic acid,,thioacetamide, thiosalicylic acid, p-sulfhydril-benzene sulfonic acid, thiopropionic acid, p-sulfhydril-phenylacetic acid.

Compounds according to the present invention correspond to the formula N Sb=D ll, AB

2 wherein X and Y may be equal or different and may represent halogens or residues of any inorganic or organic, aliphatic or cyclic, isocyclic or .heterocyclic, monocyclic or polycylic molecule containing an active hydi'ogen atom capable of reacting with a cyanuric halide with the formation or hydrogen halide. For example, X and Y may be selected from the group consisting of Cl, Br, J, F, H, -OI-I, O-alkyl,, Oacyl, --NH2, NH alkyl, N alkylz, NH acyl, -NHNH2, -NHNH-alky1, -N',alky1--NHz, NalkylNH-alkyl, NH- NH-acyl --N-acyl-I TI-Iz, Nacyl"-NI-Iacyl NHaryl, NH(CH2)nCONH2 NH-(CH2) n-NHZ, NH(CH2) nNI-Ialkyl NH (CH2) nNdialkyl, NH(CH2)11,0H NHCHzCHOHCHzOH, NHOH, NHCN residues of cyanamide derivatives, residues of substituted guanidines, amino-derivatives of carbohydrates, particularly amino-derivatives of monosaccharides, such as glucose-amine, SH, substituents of the type -SR wherein R stands for any aliphatic or cyclic group capable of carrying a SH group, such as thioglycolic acid and thiophenol, alkyl radicals and their substitution products, isocyclic and heterocyclic radicals, which may be monocyclic or polycyclic, and their substitution products, such as O-aryl groups, substituted aryl radicals, such as those corresponding to the formula wherein A and B may represent equal or difierent substituents defined further below, and E may represent a radical being in ortho-, meta or para-position to the NH or NH-NH group, and selected from the group consisting of -SO3I-I, S-OzNI-Iz, GOOH. X and/or Y may also stand for radicals of the formula Sb=D A B or for 1,3,5-triazine groups or residues of triazine derivatives. These radicals and said triazine groupsor residues of triazine derivatives standing for X and/or Y may be linked directly or indirectly to the ring carbon atoms of the first or central triazine ring. In the latter case, the link between the substituting X, Y radical. and the ring carbon atom or the first or central triazine ring may be formed by a cyclic or aliphatic amine radical, for example by an NHaryl,

NHalkyl, NHNHaryl or NI-INH-a1kyl radical. The link between the first or central triazine ring standing for X and/ or Y may be formed by an NH, NHNH group or an aliphatic or cyclic diamine, for example of the formula NHC6H4-NH or NHCH2CH2-NH-.

A and B may be the same or different, and are selected from the group consisting of hydrogen, halogen, NO2, OH, -Oalkyl, -amino-, substituted amino-, and alkyl radicals. The antimony-containing group may be in ortho-, metaor para-position with respect to the -NH group.

The compounds embodying the present invention may be prepared by reacting a derivative of 1,3,5-triazine containing at least one active halogen with an aminophenyl compound carrying a radical of trivalent antimony. The compounds according to the invention may also be obtained by reacting a halogen-phenyl compound carrying a. radical of trivalent antimony with a triazine derivative containing at least one amino-group with active hydrogen. Furthermore, compounds according to this invention may also be obtained by preparing a triazinyl-amino-phenyl-compound carrying in the aminophenyl-group a trivalent antimony radical and interchanging one or more active atoms linked to the triazine ring, or to the benzene ring or to the antimony radical with other suitable radicals. Compounds of the general formula N if NET-( C-NH I N I I Sb=D may be, for example, obtained by refluxing a compound corresponding to the formula I I NH N sb=D in a non-oxidizing atmosphere with aqueous alkali solution. Or a compound corresponding to the formula on N/ N I C-Cl and prepared by treating cyanuric chloride at 10-20 C. with aqueous alkali hydroxide, neutralizing the reaction mixture and heating it then with concentrated aqueous ammonia at about 50 C., may be condensed with a compound of the formula 4 may be obtained by subjecting, for example, a compound corresponding to the formula ea .I NH

\N I 1 SbO to the action of a suitable reducing agent, such as stannous chloride or hypophosphorous acid (H2PO3) in hydrochloric acid solution in the presence of HJ, or sodium hydrosulfite (Na2S2O4) in alkaline solution.

Example I.A solution of 16.5 parts by weight of [3-aminophenyl]-stibinous dichloride hydrochloride in 300 parts by weight of water is added dropwise to a fine suspension of 9.22 parts by weight of 2,4,61trichloro-1,3,5-triazine (cyanuric chloride) in 400 parts by weight of water under cooling and vigorous stirring for about 1 hour. The reaction takes place according to the following scheme:

SbClz Upon the addition of dilute ice-cold aqueous ammonium hydroxide, the corresponding 2,4-dichloro 1,3,5 triazinyl (6) aminophenylantimony oxide of the formula SbO is formed and may be separated from the liquid as a white precipitate. This compound may be converted into the corresponding 2-chloro-4- amino-1,3,5-triaziny1 compound by subjecting it to the further action of ammonia in a non-oxidizing atmosphere. For example, the above mentioned moist white precipitate is covered with times the quantity of 10% ammonia and shaken at 45 C. for about 1 hour, the excess ammonia is removed under reduced pressure and finally the reaction mixture is acidified with acetic acid. The resulting 2-chloro-4-amino-1,3,5-triazinyl-(G)-aminophenyl-antimonyoxide is sparingly soluble in aqueous solutions of alkali hydroxides, and in excess dilute hydrochloric acid. By treating the above described 2,4-chloro-1,3,5- triazinyl-(6) -aminophenyl stibinous compounds with aqueous ammonia under pressure, both Clatoms of the triazine ring may be substituted by NH2 groups. Furthermore, one or both of these Cl-atoms may be interchanged with substituted amino-groups by treating the chloro-triazine derivatives for example with alkylamines, hydroxy-alkyl amines or dialkylamino-alkyl amines.

Example II.-'7.3 parts by weight of chlorocyanuric-diamide are refluxed with a solution of By the action of dilute, ,coild' aqueous Hil ItOH. this compound may be converted into the portespending antimony oxide compound.

Example UL-116.88 .parts'by weight of 3-aminofilehydroxyephenyldichlorostibine hydrochloride of the formula onaC -st 0125101 are dissolved in 1000 part-s by weight of 1% aqueous hydrochloric acid and refluxedwith 7.3 parts by weight of chloro c-yanuric-diamide in a nonoxidizing atmosphere 'until the reaction of primary amine 'in the solution has become negative. The solution is then cooled in an ice bath, and precipitated by a current .pf HCl gas passed through the-solution. The precipitate thus obtainedporresponds "to the formula .ITCH:

sbionnoi Example I V. -A solution of .16.5,;partsby weight of 4-amino-phenyl dichlorostibine hydrochloride of the formula in :900 parts by weight -of 1% aquenus ,hndrochloric acid are refluxed with 7.3 parts hy vueight "of .chloroecyanuric zdiamide in :a hotl -oxidizin atmosphere until the reaction of primary amine in the solution has become negative. When this 1 condition is obtained, the solution is cooled in an ice bath, and the cooled solution is precipitated by passingastream of HCl gas through the same. The precipitate thus obtained consists of a compound corresponding to \the formula N H'zNfe tL-u Osncanm N 'Erample V;--A triazine derivative of the {formula i 0 N N Nit-c I Sb=(S.CH1C 0 OK):

may foe obtained icy-reacting the 12:,4 amino-1&5- triazine-(fi)-aniinophenyl-:dichlorostibine hydro chloride obtained in accordance with the above Example .11, with potassium ithiog'lycdlate. In order to prepare said 'triazine derivative, 1.4.318. of the compound corresponding to the above formula are added to an aqueous solution of 2.6 g. ofpotassium thioglycolate. The mixture is moderately heated in a non-oxidizing atmosphere and is adjusted to apHoi about 8.0 with NazCOs. From the solution .thus .obtained the free acid may be precipitated by acidifying, for example by the introduction of S02 gas.

.By using an equivalent amount of sodium .thi salibylateriinstead of the potassium thioglycolate in theyabcve example, a compound corresponding to =iormula Sb- CS-C 5114C QH) 3 may .be :obtained in a substantially similar manner.

Extzmple'VL-IA g. of p-aminophenyl stibinous chloride are suspended in 4500. of .methylalcohol. fIlhe suspensionis mixed with a solution of 1.0.g. of thioglycolic acid in methyl alcohol. The re action mixture is heated on the steam hathtor l hOlll', fi-lte-ieed (and allowedlto cool. .On cooling, a rreaction product .formed according .to .the tollowing scheme separates as a precipitate:

run-Osman znscmcoon norumQsn= scmo 0 on compound is soluble indilute. aqueous .so- ;dium bicarbonate, sodium hydroxide, potassium hydroxide, .diethylamine. it .is. insoluble in-chlo- .roform and ether. It .is precipitated .from. its

alkaline solution on acidifying with acetic or mineral acids, but is redissolved in excess dilute mineral acid. Dissolved in an excess of strong alkali it gives a purple color on' addition of sodium nitroprussate. It decolorizes hot Fehling solution and dissolves without color in concentrated sulfuric acid. It has av high therapeutic index amounting up to 20-25 in experimental trypanosomiasis (Trypanosomu equiperdum) in the mouse. One single well toIerated dose of its 7 water-soluble alkali salts causes in rabbits the spirochetes to disappear in syphilitic chancres within 24 hours.

Example VII.2.8 g. of a condensation product corresponding to the formula coon /s HCLHzN-O-Si 30 OH and obtained by reacting one mol of p-aminophenyl stibinous chloride with 2 mols of thiosalicylic acid are reacted with chlorocyanurio diamide substantially in the manner described in Example VI. The reaction product thus formed corresponds to the formula The product thus formed is soluble in dilute aqueous solutions of NaHCO; and NaQCOs.

Analogous products in which the trivalent Sbatom carries -SR radicals consisting of the residues of thioglycolamide, thiopropiomc acid, 8- mercapto-quinoline, 2-mercapto-pyridine, cysteine or gluthatione may also be prepared according to the above described methods.

Example IX.3.5 g. of 4-chloro- 3 aminophenyl stibinous chloride hydrochloride are dissolved in 200 g. of 1% aqueous hydrochloric acid and refluxed with 1.5 g. chlorocyanuric diamide in a non-oxidizing atmosphere until the reaction of primary amine has become negative in the solution. The solution is then cooled in an ice bath, and then precipitated by the introduction of HCl gas. The precipitate corresponds to the formula 01 N N I 'It will be understood that this invention may be carried out in other specific ways than those herein set forth, and the examples should be, therefore, considered as illustrative and not restrictive within the spirit of the invention as defined in the appended claims.

It is to be understood that the terms "amino radical or group and aminophenyl radical or group are used in the present specification and claims to include unsubstituted as well as the above disclosed substituted amino radicals and aminophenyl radicals.

Reference is made to my co-pending application Serial No. 506,564, filed October 16, 1943.

Iclaim:

1. A new 1,3,5-triazine compound consisting of a 1,3,5-triazine ring, one ring carbon atom of which is linked to an aminophenyl group substituted in the benzene ring by a radical of the formula -Sb=D wherein D represents a radical selected from the group consisting of O, S and dihalides and the substituents of the other triazine ring carbon atoms are selected from the group consisting of amino, halogen and OH radicals.

2. A new 1,3,5-triazine compound of the formula 1 Sb=D A B wherein A and B are selected from the group consisting of H, halogen, amino, and -OH radicals, and D represents a divalent radical selected from the group consisting of O, S, and dihalides.

3. A new 1,3,5-triazine compound of the formula wherein A and B are selected from the group consisting of H, halogen, amino, and OH radicals, and D represents a divalent radical selected from the group consisting of O, s, and dihalides.

4. A new 1,3,5-triazine compound of the formula wherein A and B are selected from the group consisting of H, halogen, amino, and --OH radicals.

6. A new 1,3,5-triazine compound of the formula 1TIH2 wherein A and B are selected from the group consisting of H, halogen, amino, and OH radicals.

7. In a process for preparing a 1,3,5-triazine compound consisting of a 1,3,5-triazine ring one ring carbon atom of which is linked to an aminophenyl group substituted in the benzene ring by a radical of the formula Sb=D wherein D represents a radical selected from the group consisting of O, S and dihalides, the step comprising reacting a 1,3,5-triazine derivative substituted at one carbon ring atom by a Z-substituent selected from the group consisting of halogen and amino radicals, while the other carbon ring atoms of the triazine derivative are substituted by a radical selected from the group consisting of amino, halogen and OH radicals, with a substituted. phenyl-antimony compound of the formula l Sb=D A B wherein D represents a radical selected from the group consisting of O, S and dihalides, and A and B are selected from the group consisting of H, halogemamino and -'-0I-I radicals, the step comprising reacting cyanuric chloride with an aminophenyl-antimony compound of the formula Sb=D A B 9. In a process for the preparation of a 1,3,5- triazine derivative of the formula lTTHn 0 wherein D represents a. radical selected from the group consisting of O, S and dihalides, and A and B are selected from the group consisting of H, halogen, amino and -OH radicals, the step comprising reactingchloro-cyanuric diamide with an amino-phenyl-antimony compound of the formula wherein D represents a radical selected from the group consisting of O, S and dihalides, and A and B are selected from the group consisting of H, halogen, amino and OH radicals, the step comprising reacting cyanuric chloride with an aminophenyl-antimony compound of the formula H2N- I I Sb=D A B to form a dichloro-triazinyl-aminophenyl-antimony compound and subjecting the latter to the action of ammonia.

ERNST A. H. FRIEDHEIM. 

